P6: RATIONAL DESIGN OF NOVEL NATURAL PRODUCT-DERIVED CANNABINOID LIGANDS

P6：新型天然产物衍生的大麻素配体的合理设计

• 批准号: 8167946
• 负责人: Robert J Doerksen
• 金额: $ 17.24万
• 依托单位: UNIVERSITY OF MISSISSIPPI
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167946
• 关键词: Agonist; Biological Factors; CNR2 gene; Cannabinoids; Categories; Computer Retrieval of Information on Scientific Projects Database; Computing Methodologies; Data; Development; Docking; Ensure; Funding; Grant; Institution; Ligands; Literature; Modeling; Modification; Molecular; Quantitative Structure-Activity Relationship; Research; Research Personnel; Resources; Screening procedure; Source; Study models; United States National Institutes of Health; base; design; improved; in vitro activity; novel; pharmacophore; receptor; three dimensional structure; virtual

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. For this proposal, the hypothesis is that intensive ligand-based computational methods will yield improved understanding of the requirements for effective and selective CB1/CB2 inhibition and will provide a rational guide for novel CB ligand development. The specific aims are: Aim 1. Develop four classes of pharmacophore models for CB1 and CB2 agonists and antagonists, based on all CB ligand and activity data available in the literature. The pharmacophore models will be cross-compared to gain understanding of requirements for receptor selectivity. Aim 2. Use the best pharmacophore models from Aim 1 for virtual screening to identify novel CB ligands in the different categories. Aim 3. Using CB1 and CB2 in vitro activity data for novel ligands, develop quantitative structure-activity relationship (QSAR) models to aid understanding of the molecular basis for the activity and selectivity and to provide a rational guide to modification of ligands for enhanced activity and selectivity. Though not specifically emphasized in the original proposal, we are proceeding with limited modeling of the CB1 and CB2 receptor three-dimensional structure and ligand docking studies, in order to aid the ligand-based modeling studies of Aims 1 and 3 and to ensure that we have as comprehensive an approach as possible to the rational search for novel CB ligands.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 对于此提案，假设是，基于密集配体的计算方法将提高人们对有效和选择性CB1/CB2抑制的要求的理解，并将为新型CB配体开发提供合理的指南。具体目的是：目标1。基于文献中提供的所有CB配体和活动数据，开发了CB1和CB2激动剂和拮抗剂的四类药效团模型。药效团模型将被跨X型模型，以了解对受体选择性需求的理解。 AIM 2。使用AIM 1中的最佳药效团模型进行虚拟筛选，以识别不同类别中的新型CB配体。 AIM 3。使用CB1和CB2在体外活性数据中进行新型配体，开发定量结构 - 活性关系（QSAR）模型，以帮助理解活性和选择性的分子基础，并为修改配体的合理指南，以增强活性和选择性。 尽管不是在原始提案中明确强调的，但我们正在对CB1和CB2受体的三维结构和配体对接研究进行有限的建模，以帮助基于配体的目标1和3的基于配体的建模研究1和3，并确保我们尽可能全面地搜索新的CB Ligands。